The overall objectives of this project are to study the behavioral effects, neuroanatomical substrates, and the mechanisms of action of peripheral and central administration of TRH in rodents. This project was initiated for several reasons: 1) to assist the clinical investigations utilizing TRH as an antidepressant medication in drug-refractory patients by examining behaviors in animals that have known neurochemical or neuroanatomical substrates; 2) to further investigate whether TRH is an endogenous anticonvulsant and whether it is related to the loss of carbamazepine's anticonvulsant effects following time-off or tolerance in the amygdala-kindled seizure model; and 3) to determine whether tolerance develops to TRH's behavioral effects; preliminary data in patients indicate that this may occur. If so, methods for delaying, preventing, or reversing tolerance would be attempted. Significant findings to date include demonstration of the following: 1) dose- dependent increases in locomotor activity produced by intraperitoneal (i.p.) TRH; 2) a potentiation of cocaine-induced hyperactivity by i.p. TRH during the day but not at night; 3) a decrease in the startle response, but no change in pre-pulse inhibition of startle; 4) a decrease in pentobarbital-induced sleep time; 5) no tolerance to repeated i.p. TRH in startle or activity following 8 days of injection; 6) blockade of many of TRH's behavioral effects by thyroidectomy; 7) a failure of chronic T3 replacement to reinstate TRH's effects in thyroidectomized animals; 8) no effect of acute T3 on cocaine-induced hyperactivity; 9) a moderate anticonvulsant effect of TRH injected into the hippocampus in kindled rats stimulated at threshold and suprathreshold intensities.